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Chapter 6 : Molecular Mimicry and Heart Disease

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Molecular Mimicry and Heart Disease, Page 1 of 2

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Abstract:

Heart diseases are the most prevalent cause of morbidity and mortality in rich countries. A common cause of progressive heart disease, heart failure, and sudden death is dilated cardiomyopathy (DCM), a group of disorders in which the heart muscle is weakened and cannot pump effectively. infections, in particular, are epidemiologically linked to human heart disease. infections cause pneumonia and conjunctivitis in children and are a primary cause of sexually transmitted diseases and female infertility. The development of a murine model of autoimmune myocarditis was based on genetic differences among inbred mouse strains in the immune response to CVB3-induced myocarditis. Experimental induction of most autoimmune diseases requires CD4 T-helper cells responsive to the self-antigen presented on major histocompatability complex (MHC) class II molecules, and administration of monoclonal antibodies (MAbs) against CD4 molecules can block disease in experimental and genetic animal models of autoimmunity. Hence, CD4 T-helper lymphocytes appear to be crucial regulators for the initiation of T-cell-dependent autoimmunity, and clinical trials that target the CD4 cell lineage are under way in an examination of treatments for various human autoimmune diseases. Chronic heart diseases in humans have been linked to certain HLA alleles, such as HLA-DQ6. Experimental in vivo and in vitro data provide evidence of molecular mimicry between bacterial antigens and heart-specific proteins and indicate that bacterial peptides can trigger tissue-specific inflammation of the heart. After initiation of the inflammatory process by CD4 T cells, CD8 cells and macrophages are recruited into the heart muscle and contribute to disease pathogenesis.

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6

Key Concept Ranking

MHC Class II
0.59089917
Immune Systems
0.55327564
MHC Class I
0.5217366
Human immunodeficiency virus 2
0.48474982
0.59089917
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Figures

Image of Figure 1
Figure 1

Inflammatory heart disease in BALB/c mice that were immunized with the endogenous mouse M7Aα peptide from the a myosin heavy chain (A), the control endogenous M7ApS peptide from the homologous region of the β-myosin heavy chain (B), the 60-kDa CRP-derived peptide from (ChTR1) (C), and the 60-kDa CRP-derived peptide from (ChPN) (D) ( ). Hearts were analyzed 21 days after the initial immunization. Hematoxylin-eosin staining was used. Magnifications, X320. (For color version of figure, see Color Plates, p. 275.)

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
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Image of Figure 2
Figure 2

Blood vessels in mice immunized with 60-kDa CRP-derived peptide. (A) Thickening of the arterial wall and perivascular fibrotic changes in mice immunized with ChTR1. Note the perivascular mononuclear inflammatory cells. (B) Normal morphology of the cardiac artery in mice immunized with Freud's complete adjuvant (FCA) alone. (C) Occlusion of cardiac blood vessels in mice immunized with ChTR1. (D) No occlusions in cardiac blood vessel were seen in control mice immunized with FCA alone. (A and B) Elastica staining for collagen (red) for detection of fibrotic changes. (C and D) Hematoxylin-eosin staining was used. Magnifications, X320. (For color version of figure, see Color Plates, p. 275.)

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
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Image of Figure 3
Figure 3

Serum IgG antibodies reactive to cardium-specific epitopes and ChTR1. Specific antibody production was determined by enzyme-linked immunosorbent assay ( ). OD 405. optical density at 405 nm.

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
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Figure 4

Serum IgG antibody production in -infected mice. Eight-week-old female BALB/c mice were inoculated either intranasally or intravaginally with the indicated doses of MoPn inclusion-forming units (IFU) ( ). At 36 days (intranasal infection) or 42 days (intravaginal infection) after the inoculation, serum was collected and specific IgG antibody production was determined by enzyme-linked immunosorbent assay. OD 405, optical density at 405 nm.

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
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References

/content/book/10.1128/9781555818074.chap6
1. Bachmaier, K.,, N. Neu,, L. M. de la Maza,, S. Pal,, A. Hessel,, and J. M. Penninger. 1999. Chlamydia infections and heart disease linked through antigenic mimicry. Science 283:13351339.
2. Bachmaier, K.,, N. Neu,, C. Pummerer,, J. Ionescu,, G. Duncan,, T. W. Mak,, T. Matsuyama,, and J. M. Penninger. 1997. iNOS expression and nitrotyrosine formation in the myocardium in response to inflammation is controlled by the interferon regulatory transcription factor 1 (IRF-1). Circulation 96:585591.
3. Bachmaier, K.,, C. Pummerer,, I. Kozieradzki,, K. Pfeffer,, T. W. Mak,, N. Neu,, and J. M. Penninger. 1997. Low-molecular-weight tumor necrosis factor receptor p55 controls induction of autoimmune heart disease. Circulation 95:655661.
4. Bachmaier, K.,, C. Pummerer,, A. Shahinian,, J. Ionescu,, N. Neu,, T. W. Mak,, and J. M. Penninger. 1996. Induction of autoimmunity in the absence of CD28 costimulation. J. Immunol. 157:17521757.
5. Bachmaier, K.,, N. Neu,, R. S. M. Yeung,, T. W. Mak,, P. Liu,, and J. M. Penninger. 1999. Generation of humanized mice susceptible to peptide-induced inflammatory heart disease. Circulation 99:18851891.
6. Donermeyer, D. L.,, K. W. Beisel,, P. M. Allen,, and S. C. Smith. 1995. Myocarditis-inducing epitope of myosin binds constitutively and stably to I-A(k) on antigen-presenting cells in the heart. J. Exp. Med. 182:12911300.
7. Keating, M. T.,, and M. C. Sanguinetti. 1996. Molecular genetic insights into cardiovascular disease. Science 272:681685.
8. Mason, J. W., 1998. Classification of cardiomyopathies, p. 20312038. In R. W. Alexander,, R. C. Schlant,, and V. Fuster (ed.), Hurst's the Heart, 9th ed. McGraw-Hill, New York, N.Y.
9. Neu, N.,, S. W. Craig,, N. R. Rose,, F. Alvarez,, and K. W. Beisel. 1987. Coxsackievirus induced myocarditis in mice: cardiac myosin autoantibodies do not cross-react with the virus. Clin. Exp. Immunol. 69:566574.
10. Neu, N.,, N. R. Rose,, K. W. Beisel,, A. Herskowitz,, G.-G. Gurri,, and S. W. Craig. 1987. Cardiac myosin induces myocarditis in genetically predisposed mice. J. Immunol. 139:36303636.
11. Penninger, J. M.,, N. Neu,, and K. Bachmaier. 1996. A genetic map of autoimmune heart disease. Immunologist 4:131141.
12. Penninger, J. M.,, N. Neu,, E. Timms,, V. A. Wallace,, D. R. Koh,, K. Kishihara,, C. Pummerer,, and T. W. Mak. 1993. The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules. J. Exp. Med. 178:18371842.
13. Pummerer, C. L.,, K. Luze,, G. Grassl,, K. Bachmaier,, F. Offner,, S. K. Burrell,, D. M. Lenz,, T. J. Zamborelli,, J. M. Penninger,, and N. Neu. 1996. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BABL/c mice. J. Clin. Invest. 97:20572062.
14. Smith, S. C.,, and P. M. Allen. 1992. Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis. Proc. Natl. Acad. Sci. USA 89:91319135.

Tables

Generic image for table
Table 1

Prevalence and severity of experimental autoimmune myocarditis in transgenic mice in comparison to that in wild-type controls

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
Generic image for table
Table 2

Prevalence and severity of autoimmune myocarditis induced by -derived peptides that mimic heart-specific α-myosin heavy-chain-derived peptides

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6
Generic image for table
Table 3

Peptides derived from parainfluenza virus 1- or HIV-2 with homology to heart-specific α-myosin heavy-chain-derived peptides do not cause autoimmune myocarditis

Citation: Penninger J, Bachmaier K. 2000. Molecular Mimicry and Heart Disease, p 69-82. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch6

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